N,N-dimethyl imidodicarbonimidic diamide has general name of metformin, and is a therapeutic agent for Non-Insulin Dependent Diabetes Mellitus, and a biguanide based pharmaceutical that is most excellent in hypoglycemic action and preventing the complication.
It was suggested in various articles that only metformin has a property as the first choice as oral anti-diabetic agent. In particular, the clinical effect of the metformin was proved by its pharmacological action as AMPK activator. It was reported that AMPK is a key enzyme controlling the metabolism of carbohydrate and lipid physiologically; metformin activates this enzyme, thereby normalizing high blood-glucose level, improving lipid state, normalizing menstrual irregularity, in ovulation, and treating a fatty liver; and metformin is effective in treating or preventing a cancer depleted of gene P53.
Abramson Cancer Center of Medical college, Pennsylvania reported through a professional journal for cancer that metformin is effective as AMPK activator in treating or preventing a cancer depleted of gene P53 [Monica Buzzai, et al. Systemic Treatment with the Antidiabetic Drug Metformin Selectively Impairs p53-Deficient Tumor Cell Growth, Cancer Res 2007; 67:(14). Jul. 15, 2007].
In other words, if a human body is subjected to an unfavorable condition, metformin activates AMPK enzyme, which controls an energy metabolism applied to the condition, thereby controlling glucose and lipid, and removing cancer cells.
Gene P53 renders a damaged cell or an unnecessary cell and an aged cell to kill itself (apoptosis). If a cancer cell is mutated, the gene P53 is depleted, thereby forming incurable cancer cell.
It was verified from experiments that metformin activates the AMPK enzyme of an incurable cancer cell depleted of the gene P53, thereby changing the metabolic path, and accordingly, the cancer cell is killed since it could not adapt itself to the changed metabolic path.
The report suggests that gene P53 removes a cancer and maintains longevity by employing an energy metabolism control enzyme named as AMPK.
Metformin is a drug that activates the AMPK thereby normalizing glucose and lipid metabolism. It was found that if metformin is administered to a cancer depleted of the gene P53, the energy metabolic path for the cancer cell is changed, and anticancer action increases proportionally to a dosage of metformin, and further metformin is effective in treating a cancer in a normal dosage for treating diabetes mellitus.
Further, researchers of the medical center of Beth Israel Deaconess, Boston, United States reported through a professional medical journal that metformin is effective as PGC-1α activator in preventing severe side effects such as myalgia, muscle cell damage and rhabdomyolysis [Jun-ichi Hanai, et al. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity, J. Clin. Invest. 117: 3940-3951 (2007)].
Expression of Atrogin-1 gene causes muscle toxicity such as myalgia, muscle cell damage and rhabdomyolysis, but metformin inhibits the expression of Atrogin-1 gene due to PGC-1α transcription factor activity, thereby inhibiting and preventing muscle disorder due to the increase of the expression of Atrogin-1 gene.
Metformin is administered in the form of pharmaceutically acceptable acid addition salt since metformin is pharmaceutically useful in the form of a free base, but the stability of the form is low.
Korean Patent No. 90,479 describes that four physicochemical standards such as (1) excellent solubility; (2) excellent stability; (3) non-hygroscopicity; and (4) the processibility as a tablet form must be satisfied for preparing in the form of pharmaceutically acceptable salt. It is very difficult to satisfy the four standards as a pharmaceutically acceptable acid addition salt.
Research for addition salt other than metformin hydrochloride has been performed. U.S. Pat. No. 3,957,853 discloses metformin acetyl salicylic acid salt, U.S. Pat. No. 4,028,402 discloses a novel addition salt of biguanide compound, and U.S. Pat. No. 4,080,472 discloses the preparation of metformin chlorfibric acid salt and treatment of diabetes mellitus related diseases. Further, U.S. Pat. No. 6,031,004 describes a medical composition by fumarate, succinate and maleinic acid of metformin, and its use. Although the research for metformin addition salt has been continuously performed, metformin is approved in only a drug as hydrochloride, and is widely prescribed as a therapeutic agent for non-insulin dependent diabetes mellitus. Metformin hydrochloride is the material that is almost exclusively absorbed in upper small intestine. Accordingly, it is incompletely absorbed in lower small intestine, and thus it is a salt very difficult to formulate as a controlled release drug for 24 hours. This is why the solubility of metformin hydrochloride is high (Marathe, P. et al., Br. J. Clin. Pharmacol., 50:325-332 (2000)).
Research for addition salt other than metformin hydrochloride has been performed. U.S. Pat. No. 3,957,853 discloses metformin acetyl salicylic acid salt, U.S. Pat. No. 4,028,402 discloses a novel addition salt of biguanide compound, and U.S. Pat. No. 4,080,472 discloses the preparation of metformin chlorfibric acid salt and treatment of diabetes mellitus related diseases. Further, U.S. Pat. No. 6,031,004 describes a medical composition by fumarate, succinate and maleinic acid of metformin, and its use. However, the preparation method and composition of metformin acetate had not been mentioned in the prior patents. Further, there is no known or progressed research for the effect of metformin acetate.
Although the research for metformin addition salt has been continuously performed, only metformin hydrochloride is actually used. Hydrochloride salt is large in its unit dosage and its formulation size is very large. Accordingly, even though a novel addition salt is attempted, its molecular weight and formulation becomes too large, and thus it is inferred that it is difficult to formulate. Accordingly, it is considered that the development of a product for a novel addition salt had not been attempted.
Meanwhile, prior patent (U.S. Pat. No. 4,080,472) describes that when metformin free base is prepared, an ion exchange resin column is used for removing hydrochloric acid from metformin hydrochloride, and prior patent describes that severe preparation condition that a solvent is refluxed with heating and filtered in hot state is required.
The usual dosage of metformin hydrochloride is 2550 mg at maximum daily, i.e., 500 mg or 750 mg tablet is administered 2˜3 times with a diet a day.
Such an administration method causes drastic changes in the drug level in blood due to the properties of metformin hydrochloride having quick drug elimination rate, and such a change in drug level in blood can result in side effects and resistance to the drug. Actually, the side effects related to the use of metformin hydrochloride occur frequently in gastrointestinal tract, and the examples include anorexia, nausea, vomiting and occasionally diarrhea. Accordingly, a research for extended controlled release formulation of metformin hydrochloride is being progressed in order to decrease such side effects and improve the treating quality of the Type 2 diabetic patients.
Further, metformin hydrochloride is highly water soluble drug (>300 mg/mL, 25□), and thus if it is not designed as special formulation, excessive drop in blood glucose by drastic release phenome can be caused. Accordingly, it is considered that a controlled release tablet designed so that defined dose of the drug can be control-released for 24 hours is preferable administration form in the aspect of a patient's convenience as well as therapeutic effect.
However, metformin hydrochloride is highly soluble in water, and hardly permeates the lower gastrointestinal tract, and thus the most drug must be absorbed at upper gastrointestinal tract. Therefore, there are many problems in preparation technology for preparing special formulation for controlled release.
Many patents for controlled release tablet of metformin for overcoming such problems in the pharmaceutical technology are registered at home and abroad. Korean Patent Application No. 1999-7011439 filed in the name of Depomed Inc. describes a controlled release formulation that releases a drug for 8 hours using general high molecular polymer as a formulation for controlled release of a soluble drug. Korean Patent Application No. 2000-7010280 filed in the name of Bristol Meyer's Squibb describes 2 phase controlled release tablet suitable for controlled release of metformin having high solubility in a desired degree.
However, since the unit dosage of metformin is large, i.e., 500 to 750 mg, the total weight of the tablet is very heavy in consideration of adding a pharmaceutical excipient including a controlled release agent. Further, since the solubility of metformin hydrochloride is high, the controlled release agent to be added is also needed in much amount in order to controlled-release for desired time, and accordingly the formulation may be too large to take easily. Accordingly, it is not easy to maintain continuous controlled release of metformin hydrochloride within the size that a patient can take the tablet.
The reason why metformin acetate is selected as an anti-diabetic agent is that it can cause pharmaceutically excellent controlled release and the pharmacological effect of metformin acetate is superior to that of metformin hydrochloride.
Recently, researches for various pharmacological effects of acetate are actively progressed. Many experiments that small amount of vinegar lowers blood glucose at 30 minutes after meal by inhibiting an enzyme to degrade disaccharide to glucose in intestine have been reported.
Recently, research by Carol Johnston et al for the effect of vinegar performed for patients having type 2 diabetes mellitus mentioned that 64% of blood glucose after meal is decreased and 34% of insulin sensitivity is also decreased in vinegar administration group among insulin resistant group [Vinegar: Medicinal uses and Antiglycemic effect Carol Johnston, et al. Medscape general medicine 2006; 8(2):61].
Further, Ogawa mentioned that acetic acid inhibits the activity of disaccharidase such as sucrase and lactase. In other words, he mentioned that acetic acid plays a role in decreasing blood glucose by inhibiting the action of an enzyme degrading polysaccharide to monosaccharide.
References
1. Ogawa N, Satsu H, Watanabe H, et al. Acetic acid suppresses the increase in disaccharidase activity that occurs during culture of caco-2 cells. J. Nutr. 2000 March; 130(3):507-13
2. Carol S. Johnston, PhD, R D; Cindy A. Gaas, B S. Vinegar: Medicinal Uses and Antiglycemic Effect, Medscape General Medicine. 2006; 8(2):61.
3. Ostman E, Granfeldt Y, Persson L, Björck I. Vinegar supplementation lowers glucose and insulin responses and increases satiety after a bread meal in healthy subjects. Eur J Clin Nutr. 2005 September; 59(9), 983-8.
4. Johnston C S, Kim C M, Buller A J. Vinegar improves insulin sensitivity to a high carbohydrate meal in subjects with insulin resistance or type 2 diabetes. Diabetes Care. 2004 January; 27(1):281-2.
5. Leeman M, Ostman E, Bjorck I. Vinegar dressing and cold storage of potatoes lowers postprandial glycaemic and insulinaemic responses in healthy subjects. Eur J Clin Nutr. 2005 November; 59(11):1266-71.
6. Ebihara K, Nakajima A. Effect of acetic acid and vinegar on blood glucose and insulin responses to orally administered sucrose and starch. Agric Biol. Chem. 1988; 52:1311-1312.
7. Brighenti F, Castellani G, Benini L, et al. Effect of neutralized and native vinegar on blood glucose and acetate responses to a mixed meal in healthy subjects. Eur J Clin Nutr. 1995 April; 49(4):242-7.
Korean Patent Application No. 2004-7013025 filed by Mitsukan Company, Japan describes a food and medical composition for preventing hypertension characterized in that minute amount of acetic acid shows excellent action of lowering blood pressure by oral intake for a long period.
Researches for vinegar and acetic acid itself on various diseases have been actively performed. However, the research shows considerable effects as outcome of the research for vinegar as food not experiment for acetate, it did not show the effect as metformin acetate as shown in the present invention, and it did not mentioned the effect for interaction with metformin.
The present inventors decided that departing from the paradigm that the problem of metformin hydrochloride must be overcome by designing a formulation through selecting a proper controlled release agent, if the solubility of the active ingredient is lowered, side effects such as excessive drop of blood glucose level or a disorder in gastrointestinal tract is improved even on taking immediately release tablet, and more efficient controlled release can be performed on formulating the immediately release preparation; and studied on metformin addition salt having relatively low solubility to water. However, there is a problem in practicability since if the molecular weight of a novel metformin derivative is very high compared to metformin hydrochloride even though a metformin derivative having low solubility is synthesized, the dosage of metformin is increased. This is a crucial problem on considering the unit dosage of metformin is large. If a metformin addition salt, which has not too large molecular weight thereby having dosage capable of being compressed as a tablet, is easy to be control-released due to lowered solubility, and has relatively excellent permeability at lower gastrointestinal tract and colon, and thus has relatively wide absorption site compared to metformin hydrochloride, is developed, it will have excellent ripple effect pharmaceutically or pharmaco-dynamically.